One of the most important concepts to emerge in recent years in opiate research is the possibility of multiple classes of opioid binding sites. Originally proposed as "receptor dualism", this concept was next expanded to account for the different pharmacological syndromes produced by three general classes of opiates (mu, kappa and sigma) and finally the enkephalins (delta). Soon afterwards studies of the binding characteristics of radiolabeled drugs from all these classes yielded results consistent with binding site heterogeneity. We propose to continue our investigations into the biochemical characterization of these postulated binding subtypes and, in addition, to try to correlate various binding sites with pharmacological actions. This correlation is our ultimate goal. Binding sites per se have little relevance unless they can be of use in understanding the pharmacological properties of drugs. We, therefore, plan both in vitro and in vivo approaches to this question. In vitro we will investigate the binding characteristics of a number of radiolabeled drugs from the four major classes (mu, kappa, sigma and delta). Two general techniques will be used. In the first, we will study binding in brain homogenates. The different ligands will be compared pharmacologically and biochemically. Additional studies will look into the developmental appearance of possible receptor subtypes and phylogenetic differences. We also plan to perform autoradiography using the same ligands. Again, we will compare them pharmacologically and biochemically. However, autoradiography permits us to study the regional localization of receptors at a level unobtainable with homogenate studies. This is important. Other laboratories have demonstrated significant differences in the regional localization of mu and delta binding sites. We also plan to look into the actions of a series of long-acting opiate agonists and antagonists both in vitro and in vivo. In vivo our major aims are to investigate analgesia and respiratory depression. We plan to study a number of drugs from the different classes and use these results to correlate their actions with possible binding subtypes. Ultimately, these studies will hopefully lead to a better understanding of pain and its control.